The hu
man proteins ciliary neurotrophic factor (CNTF) and interleukin-6 (IL6) and their receptors share structural ho
mology with leptin and its receptor. In addition, uncoupling protein-2 (UCP2) has been shown to participate the regulation of leptin on food intake. All three proteins are active in the hypothala
mus. Experi
ments have shown that CNTF and IL6, like leptin, can influence body weight in hu
mans and ani
mals, while the effect of UCP2 is not consistent. In a Dutch general population (n = 545) we investigated associations of CNTF (null G/A, rs1800169), IL6 (174 G/C, rs1800795) and UCP2 (A55V, rs660339 and del/ins) poly
morphis
ms with weight gain using interaction graphs and logistic regression analysis. The average follow-up period was 6.9 years. Individuals who gained weight (n = 264) were co
mpared with individuals who re
mained stable in weight (n = 281).
In women the CNTF polymorphism (odds ratio (OR) = 2.15, 95 % CI: 1.27–3.64, p = 0.004) and in men the IL6 polymorphism by itself (OR = 2.26, 95 % CI: 1.08–4.75, p = 0.03) or in combination with the CNTF polymorphism, were associated with weight gain. Furthermore, CNTF and IL6 polymorphisms in interaction with UCP2 polymorphisms had similar strong effects on weight gain in women and men, respectively. All observed effects were statistically shown to be independent of serum leptin level. These results are incorporated in a biological model for weight regulation with upstream effects of CNTF and IL6, and downstream effects of UCP2.
The results of this study suggest a novel mechanism for weight regulation that is active in both women and men, but strongly influenced by sex.